Studying Lipophilicity Trends of Phosphorus Compounds by ³¹P-NMR Spectroscopy: A Powerful Tool for the Design of P-Containing Drugs

Abstract

Systematically studying the lipophilicity of phosphorus compounds is of great importance for many chemical and biological fields and particularly for medicinal chemistry. Here, we report on the study of trends in the lipophilicity of a wide set of phosphorus compounds relevant to drug design including phosphates, thiophosphates, phosphonates, thiophosphonates, bis-phosphonates, and phosphine chalcogenides. This was enabled by the development of a straightforward log P determination method for phosphorus compounds based on 31P-NMR spectroscopy. The log P values measured ranged between −3.2 and 3.6, and the trends observed were interpreted using a DFT study of the dipole moments and by H-bond basicity (pK HB) measurements of selected compounds. Clear signal separation in 31P-NMR spectroscopy grants the method high tolerability to impurities. Moreover, the wide range of chemical shifts for the phosphorus nucleus (250 to −250 ppm) enables a direct simultaneous log P determination of phosphorus compound mixtures in a single shake-flask experiment and 31P-NMR analysis.

Placing CF2 in the Center: Major Physicochemical Changes Upon a Minor Structural Alteration in Gem‐Difunctional Compounds

“…However, when this exchange is made at the α-position to functional groups, such as P=O, C=O and so on, the electronegativity of the additional oxygen (O-X=O) may strongly affect the electronic properties. For instance, the lipophilicity enhancement via a reduction of the H-bond basicity, which was observed for the transition from bis-phosphonate 14 b to diphosphate 14 a, is consistent with our previous observations for the related transitions from phosphonate to phosphate [50] or from ketone to ester. [7]…”

“…Lipophilic bisphosphonates are a branch of this unique family of drugs that might extend their therapeutic range, for instance, for cancer chemotherapeutics [49] . It is worth noting that the accurate experimental lipophilicities of both lipophilic‐ and hydrophilic bisphosphonates were rarely reported, presumably due to limitations of the traditional log D determination methods [50] . Hence, as part of a novel 31 P NMR‐based log P determination method developed by us very recently, we studied, inter alia, lipophilicity trends of bis‐phosphonates series [50] .…”

“…It is worth noting that the accurate experimental lipophilicities of both lipophilic‐ and hydrophilic bisphosphonates were rarely reported, presumably due to limitations of the traditional log D determination methods [50] . Hence, as part of a novel 31 P NMR‐based log P determination method developed by us very recently, we studied, inter alia, lipophilicity trends of bis‐phosphonates series [50] . In addition, we have also assessed the effect a CH 2 /CF 2 replacement has on the log P of a phosphonate group, as α‐fluorination of phosphonates may have additional benefits such as being non hydrolysable analogues of the bioactive phosphates [51] .…”

“…[50] Hence, as part of a novel 31 P NMR-based log P determination method developed by us very recently, we studied, inter alia, lipophilicity trends of bis-phosphonates series. [50] In addition, we have also assessed the effect a CH 2 /CF 2 replacement has on the log P of a phosphonate group, as α-fluorination of phosphonates may have additional benefits such as being non hydrolysable analogues of the bioactive phosphates. [51] The Chemistry-A European Journal conferred stability against enzymatic hydrolysis obtained by replacement with CF 2 has also been demonstrated in additional phosphorous compounds such as fluorinated deoxynucleotide analogs.…”

Perspectives on Nuclear Magnetic Resonance Spectroscopy in Drug Discovery Research

“…107 Structure−lipophilicity relationships for a wide set of phosphorus compounds were determined using a shake-flask 31 P NMR-based method. 108 The log P values ranged between −3.2 and 3.6 and were found to be in good agreement with log P/log D results from orthogonal methods (SI, Figure S25). A series of phosphates, thiophosphates, phosphonates, thiophosphonates, phosphine chalcogenides, and pesticide derivatives were evaluated, and their log P values summarized according to their structural motifs in Figure 29.…”